THE DETERMINATION OF UNEVEN PULMONARY BLOOD FLOW FROM THE ARTERIAL OXYGEN TENSION DURING NITROGEN WASHOUT

Theodore N. Finley

J Clin Invest. 1961;40(9):1727-1734. https://doi.org/10.1172/JCI104395.

Research Article

Find the latest version: https://jci.me/104395/pdf THE DETERMINATION OF UNEVEN PULMONARY BLOOD FLOW FROM THE ARTERIAL OXYGEN TENSION DURING NITROGEN WASHOUT By THEODORE N. FINLEY * (From the Cardiovascular Research Institute, University of California Medical School, San Francisco, Calif.) (Submitted for publication January 3, 1961; accepted May 29, 1961)

Many tests are available for measuring un- . The test requires the use of a nitrogen evenness of pulmonary ventilation. In recent meter and a flow-through cuvet 02 electrode for years tests of unevenness of pulmonary blood measuring arterial Po2 continuously during the flow have been described, which utilize radio- of 02. In practice the test takes ap- active krypton (1) in patients with emphysema, proximately 20 minutes and the calculations radioactive oxygen in patients with mitral steno- another 20 minutes. This method is based on sis (2), and radioactive carbon dioxide in normal the principle that the rate of rise of alveolar 02 subjects (3). These studies provide quantita- tension during oxygen inhalation depends on the tive data on the degree of unevenness of pul- distribution of inspired 02 to well and poorly monary blood flow but require expensive and ventilated regions of the (in relation to complicated apparatus and are not easily their volume), while the rate of simultaneous adapted to clinical pulmonary function testing. rise of arterial 02 tension depends on the dis- Simpler methods of estimating unevenness of tribution of pulmonary blood flow to these blood flow in relation to ventilation have been regions and the anatomical shunts. The theory, suggested. These are based on the rate of rise method and results of these studies in normal of arterial (ear oximeter) subjects and in patients with cardiac and pul- during the inhalation of oxygen (4-6), analysis monary disease are presented here. of gas samples obtained from various lobes of the lungs (7), continuous analysis of a single THEORY expiration (8), and the difference between the The lungs can be divided into a well ventilated region nitrogen tension of alveolar gas and urine (9, (which need not be homogeneous) and a poorly ventilated 10). These simpler methods do not provide region (subscripts 1 and 2, respectively). Arterial blood quantitative data on the degree of unevenness of is a mixture of blood that has passed through these regions or through venous-to-arterial shunts. Its oxygen content pulmonary blood flow. (Ca) is related to the blood flows through the capillaries of An ingenious graphical method of determining the various regions (Q1, Q2) and through the shunt (Q8), unevenness of of the lung in patients and to their respective oxygen contents (Cl, C2 and Cv) as with chronic pulmonary emphysema has been follows: worked out by Briscoe and co-workers (11). Ca QT = C1 Q1 + C2Q2 + CQ9 [1] This method utilizes a nitrogen washout and where Qi + Q2 + Qs = QT, the cardiac output. In this wash-in technique and the arterial saturation and subsequent formulations we omit, from our otherwise (luring air-. Its disadvantage is that conventional (12) symbolization, the subscript c for capil- lary and the chemical subscript 02- other causes of arterial desaturation i.e., shunts It follows from Equation 1 that at any time (t) during and diffusion barriers cause an overestimation the N2 washout: of the degree of unevenness of perfusion. In this laboratory we have devised a test Cat = C (t( ) +C2t which yields quantitative data for the deter- Q1 +Q2 Q1 +Q2 mination of the fractional alveolar ventilation (C. C.,) t -. 0.1. [2] and pulmonary capillary blood flow that go to Ql + Q2 the well and poorly ventilated regions of the Wre assume the following are constant in the later stages of the N2 washout: 1) the magnitude of the various blood * Fellow of the National Tuberculosis Association. Sup- flOwS (QI, Q2, Q., QT) relative to each other; 2) the arteri- ported in part by ITSPHS Grant H-4029. ov5eiious 02) content difference (Ca - Cv). When we then 1 727 1728 THEODORE N. FINLEY consider the difference between the final equilibrium state lated region, because the assumptions that allow the cal- at time f and the changing state at time t, it follows that: culation of PEN2 are not valid in the early portion of the N2 washout. The distribution of pulmonary blood flow is Caf - Cat = (Cf -C1)CIO matched with the distribution of alveolar ventilation when the fractional perfusion equals the fractional ventilation of the poorly ventilated region. + (C2f - C2t) ( QQ Q ) [3] The dilution index. A template was made in which log II/El + (1/n)]hn is plotted against n. This was laid Late in the washout when is fully saturated over the semilogarithmically plotted data and analyzed in all parts of the lung, further changes in 02 content are into linear components (16, 17) (Figure 1). The inter- linearly related to changes in 02 tension (13). Equation 3 section of the curved template with each straight line gives can then be formulated in terms of differences in Po2: a value of n (on the baseline) which is the dilution index. This index, which is related to the turnover rate (k) of Paf - Pat = (Pif - Pit) ( Q + ) Robertson, Siri and Jones (16) is the ratio FRC/VT - VD for each region. The use of the dilution index and its determination by a + (32f - P2f) (. Q Q )E[4] template has proved to be a useful shortcut in the calcula- tion of the functional residual capacity (FRC) and alveolar Any Po2 gradient due to diffusion difficulty becomes in- tidal volumes of the well and poorly ventilated regions. finitesimal at this time when Po2 is high in all alveoli It also provides a simple characterization of the alveolar (13-15). Alveolar and end-capillary oxygen tensions are ventilation of any region. thus identical within a region; i.e., PAI = Pi, PA2 =P2. Mixed expired alveolar versus end-tidal nitrogen concen- If Pco2 is constant within each region, then Po2 is related trations. In our study we measured end-tidal N2 concen- to PN2, provided that the total pressure of all gases is con- stant, as it is, in each region, and hemoglobin is fully satu- rated, as it is, at this time. Then:

Paf - Pat = AP1N2 (+.0 )

+ AP2N2 (CQ2) = APCN2 [5] where the various values of APN2 are the excess at time t over the final' value at timef. APCN2 is the mean value of this excess in mixed end-capillary blood. This relation holds, regardless of the number of regions. Late in the washout the concentration of nitrogen has become negligible in all but the worst ventilated region. The contributions of N2 from the inspired 02 tank and front the tissues are virtually constant; while they affect the final value they are of no significance in these considera- tions of the changes in PN2. It follows that, late in the washout: VAT APAN2 = VA2* APA2N2 and QT APaN2 = QO2AP2N2, where the subscript T refers to total alveolar ventilation or total cardiac output. Since APA2N2 = AP2N,, these two equations yield the ratio between those fractions of total alveolar ventilation and total perfusion, respectively, which are distributed to the poorly ventilated region: NO. OF BREATHS = (VA2/VAT)/(Q2/QT) APAN2/APCN2 [6] FIG. 1. PERCENTAGE OF N2 CONCENTRATION IN END- At the end of the N2 washout this ratio is constant, since EIXPIRED GAS ON LOGARITHMIC SCALE PLOTTED AGAINST semilogarithmically plotted values of APXN, and APCN2 are NUMBER OF BREATHS FOR THE WELL AND POORLY VENTI- LATED REGIONS OF THE LUNG. The dotted lines found to lie on parallel lines. When (VA2/VAT), APAN2 represent and APCN2 are experimentally determined, Q2/QT can be the N2 washouts of the well and poorly ventilated com- calculated. No attempt has been made to estimate the partments obtained from the N2 end-tidal washout. The distribution of perfusion to compartments in the well venti- dilution index template is superimposed on these graphs, giving an intercept value with the well ventilated region For present purposes we consider N2 washout complete at breath 5 and with the poorly ventilated region at breath when the forced end-expired PN2 is less than 4 mnmi Hg. 20. 1729 DETERNIINATION' OF UTNEVEN PUTLMIONARY BLOOD FLOW\

FIG. 2. RIGHT, CLARK 02 ELECTRODE (A) IN LUCITE JACKET (B) AND LEFT, THE FLOW-THROUGH CUVET (C-D) FOR THE ELECTRODE SHOWING THE HOLES (E) THAT ALLOW CIRCULATION THROUGH TUBES (F AND G) FROM THE WATERBATH AROUND CUVET AND ELECTRODE. The left-hand part fits snugly beneath the right-hand part and the membrane of the Clark electrode is in the flowing blood stream.

The fact that these concentrations exceed mixed of the N2 washout on a Severinghaus modification of the tration. in this alveolar and mixed expired concentrations does not affect Clark 02 electrode (19). The Clark electrodes used over the 0 to 95 per cent 02 our determination of the dilution indices nl and n2 (18). study were slightly alinear 21 per cent 02, But this fact does necessitate the use of an additional piece range. This alinearity occurred below in determining the absolute volumes and which affected the accuracy of the Po2 record in the earlier of information deter- ventilations of the various regions. We hav-e used the part of each study but not in the later part used in to determine alveolar *ventilation mining the distribution of perfusion. The final Pao2 used following relationship regardless of for the less ventilated alveoli (VT -VD)2: in each case was the constant highest value, the time required to attain it. - VD) was checked in dogs FRCT n1(VT [7] The reproducibility of the method (VT VD)2 = that fi - n2 in which the arterial blood from the femoral artery passed through the cuvet was returned continuously by Where FRCT, VT, and VD are, respectively, the total vein. In 3 dogs studied this way repeated N2 washouts FRC, , and . on a constant volume ventilator, and continuous recordings of Pao2 were identical for the individual dogs. METHODS AND MATERIAL The arterial Po2 tracing lagged behind the tracings re- reasons. The first was the The seated subject breathed from a system which de- corded at the mouth for two from the alveolar capillaries to the cuvet, livered air or oxygen on demand. Inspired and expired circulation time about 12 seconds; this was measured as the were sampled continuously in the mouthpiece, and which averaged gas in alveolar tension occurring dur- through an infrared CO2 meter and a N2 meter, time between the rise 02 passed the onset of the rise in both calibrated before and after each study with gases ing the first inhalation of 02 and was the slow response time of the analyzed with the Scholander gas analyzer. While the arterial Po2. The second for 90 per cent response after a subject breathed air, expired gas was collected for 3 min- electrode; the mean time rise in in either blood or gas was 9 seconds. utes in a Neoprene metereological balloon. A sample was square wave Po2 the rate of rise of the arterial 02 tension was not taken for 02 and CO2 analysis and the volume measured Because during the N2 washout, it was necessary to cor- with a Tissot spirometer. Brachial arterial blood was constant rise in tension for the electrode lag. The sampled through an indwelling polyethylene catheter. rect the rate of O0 checked by having the patient perform a Its Pco2 was measured with the Severinghaus CO2 elec- over-all lag was for several seconds at the completion of trode (19). During N2 washout studies arterial 02 tension Valsalva maneuver This maneuver causes a square-wave was measured continuously with a Clark electrode placed the N2 washout. tension in the alveolar gas almost equal to the in a temperature-controlled cuvet (Figure 2), through which rise in 02 pressure. The time for a new plateau blood flowed at a constant rate in a range of 5 to 10 ml per total rise in alveolar to occur was approximately the same The data were recorded on a Grass polygraph of arterial 02 tension minute. time for 90 per cent 3, 5 and 7). Barometric pressure was meas- as the sum of the circulation time and (see Figures separately. ured at each study and was used to calculate all tensions. electrode response, determined the following pulmonary This flow-through 02 electrode was calibrated by analyz- In addition to these studies, ing samples of arterial blood at the beginning and the end function tests were performed: 7-minute N2 washout (20); 17,30 THEODORE N. FINLEY

$5. 1-20-60 700

500 PaO2 300

100

0-/00 0-20 0-/0

% N2 so

% 6 N2

% C02 3

% 100too SATURATION 95 2 MINUTES

FIG. 3. CONTINUOUS RECORDING OF ARTERIAL 02 TENSION, END-TIDAL N2 AND CO2 CONCENTRATIONS AND EAR OXIMETER. Normal subject; inhalation of O2 begin- ning at 0 minutes.

FRC at the end of 7 minutes (20); single breath 02 test of distribution of inspired air (21); calculation of physiologi- FIG. 4. PER CENT CONCENTRATION OF END-TIDAL AND cal dead space (22); maximal inspiratory and expiratory CAPILLARY N2 PLOTTED ON LOGARITHMIC SCALE AGAINST flow rates; and, on patients with interstitial fibrosis, pul- NUMBER OF BREATHS FOR THE SAME SUBJECT OF FIGURE 3. monary (23). Anatomic dead space was estimated to be 30 per cent of the tidal volume. This value was chosen, since it represented the average PDS/ blood. The data in Table II show that the VA/Q0 VT X 100 in the normal subjects whose VT ranged from ratios are approximately the same in both the 420 to 970 ml. well and poorly ventilated regions despite the RESULTS fact that the well ventilated region has consider- Normal subjects. Figure 3 shows a typical ably more ventilation per unit alveolar volume recording. Both the N2 washout and the rise of than has the poorly ventilated compartment. arterial 02 tension are fast and "complete" in 20 The two plots are superimposable. breaths. Figure 4 shows the semilogarithmic Patients with pulmonary emphysema. Figure plot of per cent N2 in end-tidal gas and capillary 5 shows that both the rise in arterial 02 tension

BLE I Results of pulmonary function tests (mean and range)

7-min N2 PCo2 Pao5 Pao2 Groups Subjects Age FRC S. B.02* washout PDS/VT (a-A) (air) (02) Dco

no. yrs L % N2 % N2 ml/ml mm Hg mm Hg mm Hg % pred. Normal 9 31 3.1 0.7 0.5 0.30 1.5 95 645 115 21-38 2.2-3.9 0.0-2.4 0.5-0.7 0.27-0.35 1.0-4.0 85-105 610-660 102-125 Emphysema 15 59 4.4 7.2 6.9 0.51 7.0 70 585 44-76 3.1-6.2 2.1-13.0 2.3-17.2 0.33-0.67 2.0-13.0 60-90 460-640 Interstitial fibrosis 7 45 2.1 4.7 1.4 0.43 3.5 80 615 49 23-53 1.3-3.2 1.0-11.0 1.0-2.2 0.33-0.59 0.0-8.0 65-90 565-660 23-67 Mitral valv. dis. 4 43 2.2 5.0 2.3 0.44 6.0 75 600 + pulm. hypertens. 29-49 1.0-3.0 4.0-6.0 0.6-3.4 0.37-0.55 4.0-9.0 55-80 580-615 * Single-breath oxygen test. DETERMINATION OF UNEVEN PULMONARY BLOOD FLOW 1731

#R. 12-22-S9 700

5001. 300 100

a 0-/GO 0-20

% N2 m

%V' N2 % C02 3,

0 1 2 3 4 MINUTES 6_X FIG. 5. PATIENT WITH EMPHYSEMA; CONTINUOUS RE- CORDING OF ARTERIAL BLOOD 02 TENSION, END-EXPIRED CACCPATED AdVAOLA R N2 AND CO2 CONCENTRATIONS DURING INHALATION OF 02- MIJXED) EXPIRPED 2 c01ciVCErRA7r/o101 and the fall in alveolar N2 concentration are de- layed. Although the delay is greater for the blood curve, this can best be determined by plot- 0 20 40 60 8o coo 120 140 NO.. OF BRtEATHS ting semilogarithmically per cent N2 in end-tidal gas and capillary blood (Figure 6). There is a FIG. 6. PER CENT CONCENTRATION OF ENDTIDAL AND marked difference between the two, owing to CAPILLARY N2 PLOTTED ON LOGARITHMIC SCALE AGAINST NUMBER OF BREATHS FOR THE PATIENT SHOWN IN FIGURE or underventilation of the overperfusion poorly 5. The shaded area represents the portion of washout ventilated space. The shaded area represents where calculation of distribution of ventilation, perfusion the region selected for the calculation of ventila- and mean expired alveolar PN2 was performed. tion and perfusion distribution to the poorly ventilated region. Table II shows that there is a through the poorly ventilated region in terms of marked difference in ventilation-perfusion ratios percentage of total pulmonary blood flow; in of the two regions in patients with emphysema. relation to volume, this perfusion is much the The percentage of the total ventilation distrib- same as in the normal group. The reduced uted to the two regions is similar to that found VA/Q0 ratio in the poorly ventilated space is in the normal subjects, but there is a marked in- reflected in the low arterial 02 tension when these crease in the volume of the poorly ventilated patients breathe air and in the increase in PDS/ region so that the ventilation of this space is VT ratio and arterial end-tidal Pco2 differences. markedly reduced in relation to volume. In Patients with mitral valvular disease and pul- addition, there is a marked increase in perfusion monary hypertension. Two subjects had pure

TABLE II Distribution of functional residual capacity, ventilation, perfusion and the fractional ventilation to perfusion ratios of the well ventilated and poorly ventilated regions (mean and range) in normal subjects and patients with pulmonary and cardiac disease

Groups, no. Well ventilated region Poorly ventilated region FRC% VA % % VA%/Q,% FRC% IVA % QC% VA%/Q,% Normal, 9 60 82 81 1.03 40 18 19 0.92 14-100 58-100 50-100 1.00-1.16 0-86 0-42 0-50 0.84-1.00 Emphysema, 15 32 85 49 1.78 68 15 51 0.30 8-69 74-95 34-63 1.35-2.42 31-92 5-26 37-66 0.11-0.56 Interstitial 39 81 59 1.65 61 19 41 0.51 fibrosis, 7 8-89 54-94 15-87 1.05-3.60 11-92 6-46 13-85 0.14-0.91 Mitral valv. 41 83 44 2.36 59 17 56 0.31 dis. + pulm. 39-45 75-90 22-67 1.35-3.64 55-61 10-25 33-78 0.26-0.33 hypertens., 4 1732 THEODORE N. FINLEY AR. -/t-iso value over the latter part of the washout. There 700 is no reason why this should change at a time 0oo w_-hen the subject is virtually in a steady state. Pao,300 00 [ / The fourth assumption, that diffusion barriers 100 l", ! present no impediment when PAN2 is high, is % N2 valid and has already been discussed under 0 Theory. S The fifth assumption, that the Pco2 is constant,

0 though at various values in different regions, is , 2 3 4. valid in a state such as this. MINUTES steady The last assumption is that the lung can be FIG.I 7. PATIENT WITH MITRAL STENOSIS; CONTINUOUS divided into only a well and a poorly ventilated RECORD] [NG OF ARTERIAL BLOOD 02 TENSION, END-TIDAL N2 AND CO2 CONCENTRATIONS DURING INHALATION OF 02. reglon. This assumption permits the calculation of mixed alveolar PN2 from the end-tidal PN2 mitral, stenosis, and two had mitral stenosis and graph. In order to check the reasonableness of insuffic:iency. All had pulmonary hypertension this assumption, a model lung with a distribution confirnraed by pressure recordings during cardiac of ventilatory regions varying over a wide range cathete?rization. A record from a patient with was constructed mathematically. When this pure rnitral stenosis and a mean pulmonary model was subjected to a N2 washout, and the arterialI pressure of 50 mm Hg is shown in Figure alveolar PN2 was plotted on two-cycle semilog- 7. There is a very slow rise in arterial 02 ten- arithmic paper, only two regions could be found sion. Tables I and II show unequal ventilation- by the graphical technique (24). The two-ven- perfusi(on ratios similar to those found in the tilatory-region simplification is practical as well patient:s with emphysema. These findings were as convenient. The use of the 7-minute FRC to reflecte,d in the increased PDS/VT ratios, the calculate the fractional ventilation to the poorly increas(ed Pco2 differences between arterial blood ventilated region is convenient but, in patients and alvreolar gas. with chronic pulmonary emphysema, introduces a small inaccuracy. A recent study (25) has DISCUSSION shown that the conventional 7-minute FRC Inde~veloping the equations that allow calcula- measured by the N2 washout method underesti- tion of end-capillary N2 tension, several assump- mates the prolonged N2 washout FRC by 19 to tions viwere made. The first was that the pul- 48 per cent in patients with chronic pulmonary monar Z blood flow reached a fixed distribution emphysema. In this laboratory the 7-minute pattern[ late in the N2 washout; i.e., the fractional FRC measured by the N2 open-circuit and the blood fltow through the well and poorly ventilated closed-circuit methods underestimated the 18- region became constant. This merely implies minute FRC by an average of 980 ml in 13 pa- that any changes due to 02 were proceeding at a tients with chronic pulmonary emphysema (26). negligit le rate near the end of the 02 breathing Using the 18-minute rather than the 7-minute period when our determinations were made. FRC value increases the ventilation to the The pe~rfusion distribution calculated by this poorly ventilated region approximately 20 per method is that which occurs during pure ogyxen cent, or an increase from 15 to 18 per cent in the breathi ng. value VA per cent to the poorly ventilated region The ssecond assumption is that the right-to-left in Table II. anatom ical shunt becomes a fixed fraction of the The contributions of N2 from the inspired O2 pulmonLary blood flow during N2 washout. In tank and from the tissues have a virtually con- normal subjects the anatomical shunt becomes stant effect and so do not influence the various constanIt when alveolar Po2 is raised stepwise values of APN2 used here, which are differences (16). from the final state. Hence the ratio APRN2/ The t hird assumption is that the arteriovenous APEN, is not affected. 02 contit ent difference (Ca-CV) reaches a constant Measurement of arterial Po2 during the N2 DETERMINATION OF UNEVEN PULMONARY BLOOD FLOW 1 733 washout can. be nmade continuously, as here, or been shown (29) that the distribution of the pul- by drawing individual samples at different times nmonary vascular lesions in such patients is not during the washout. The accuracy of Pao2 uniform. The greatest medial hypertrophy and measurements in the high Po2 range is 4±5 mm intimal thickening is found in the bases, while Hg. The advantage of the directly recorded the apical regions of the lungs are relatively Pao2 is that Pao2, - Pao2, can be graphed over normal. It is possible that the abnormalities in the entire N2 washout and the proper range can VA/Q0 in our patients with mitral stenosis and be selected late in the washout when the slopes of pulmonary hypertension are due to these differ- PXN2 and PCN2 are parallel. ences in the pulmonary vasculature. The results show that in normal subjects the ratio of ventilation to perfusion is approximately SUMMARY the same for both the well and the poorly venti- 1. A new method is described for obtaining lated regions. This finding is in agreement with quantitative data on distribution of pulmonary the results obtained by other methods (3) and capillary blood flow through well and poorly is to be expected from the normal values for ventilated regions of the lungs. It requires con- pulmonary function obtained in these subjects. tinuous or repeated analyses of alveolar PN2 and In the patients with emphysema, there was a arterial Po2 during inhalation of 02. consistently lower ventilation-perfusion ratio in 2. End-capillary PN2 is calculated from the the poorly ventilated region. The perfusion of arterial 02 tension during the N2 washout. the two regions in the patients with emphysema 3. The ratio of PiN2 to PCN2 late in the washout was more closely related to the volume of the gives the ratio of fractional ventilation to frac- region than to its ventilation. This confirms tional perfusion through the poorly ventilated work recently published by Briscoe and associ- space. ates (11). This can be interpreted in two ways. 4. Unevenness of perfusion exists when the One is that the poorly ventilated region repre- fractional perfusion is in excess of fractional sents the more normal lung tissue which is still ventilation to the poorly ventilated space. normally perfused, while the well ventilated area 5. Normal subjects have no unevenness of per- represents tissue with increased compliance and fusion in relation to ventilation. ventilation in which there has been loss of capil- 6. Patients with emphysema have marked un- lary bed. Another is that the reverse situation evenness of perfusion in relation to ventilation exists and the poorly ventilated region represents but not in relation to lung volume. the more diseased areas in which ventilation is 7. Patients with interstitial fibrosis may have markedly inadequate and perfusion is still rela- unevenness of perfusion in relation to ventilation. tively in excess of the inadequate ventilation. 8. Patients with mitral valvular disease and Further studies are needed to establish correla- pulmonary hypertension have unevenness of tions between the physiological findings such as perfusion in relation to ventilation. ours and the anatomical distribution of the alveolar and capillary lesions in patients with REFERENCES emphysema. 1. Gurtner, H. P., Briscoe, W. A., and Cournand, A. Studies of the ventilation-perfusion relationships in The results in patients with fibrosis showed the lungs of subjects with chronic pulmonary em- great variation and are difficult to interpret. In physema, following a single intravenous injection of some patients the ventilation-perfusion relation- radioactive krypton (Kr85). I. Presentation and ships appeared relatively normal, while in others validation of a theoretical model. J. clin. Invest. the findings were similar to those in with 1960, 39, 1080. patients 2. Dollery, C. T., and West, J., B. Regional uptake of emphysema. 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